Mydriatic agents are an important class of compounds that are used to dilate the pupil. Mydriasis is required during opthalmic examinations, in order to provide for a more complete examination of the fundus, the vitreous and the periphery of the lens, and in various surgical procedures such as those reported by Freeman and Gettelfinges, American Intra-Ocular Implant Society Journal, 7,172-173 (1981) (e.g. vitrectomy, lens extraction, and intraocular lens implantation).
A clinical study reported by R. Weekers, et al., American Journal of Opthalmology, 40,666-672 (1955) concluded that reduced ocular tension results from sympathomimetic stimulation. Included in the study were such diverse sympathomimetic (adrenergic) amines as adrenalone (the corresponding ketone derivative of adrenalin) and the dextrorotatory (d) and levorotatory (1) optical isomers of adrenalin (epinephrine). The study established that 1-adrenaline (a strong sympathomimetic agent) lowered ocular tension, whereas the corresponding derivative, adrenalone and d-adrenalin (agents having only minimal sympathomimetic activity) do not. Even a 2% adrenalone solution did not cause any reduction in the intraocular pressure of patients suffering from glaucoma, and resulted in only a minimal level of mydriatic activity.
The primary objective of the prior art was to reduce the intraocular pressure in the treatment of glaucoma, an eye disease characterized by a progressive increase in intraocular pressure that occurs over a prolonged period of time. The drugs used were intended to have a long acting effect in order to keep the pressure down over a long period of time without need for readministration of the drug. If left untreated, the optic nerve will deteriorate to such an extend that blindness occurs. To reduce the intraocular pressure sufficiently to prevent damage to the optic nerve, the adrenergic amine, epinephrine, and miotics, which include certain parasympathomimetics such as pilocarpine and cholinesterase inhibitors such as physostigmine, have been applied topically to the eye. However, undesirable side effects were observed. Absorption of the topically applied drug occasionally causes systemic effects as well as localized allergic reactions. The alpha-adrenergic stimulatory action of epinephrine frequently causes mydriasis and sometimes retinal maculopathy, during prolonged usage.
Isoproterenol, another adrenergic amine, had satisfactorily reduced intraocular pressure while also causing mydriasis. However, such serious side-effects as taachycardia, weakness, and palpatations were observed so that the continued practical use of this drug in the treatment of glaucoma was prohibited. Ross and Drance, Arch. Ophthal., 83, 39-43 (1920).
U.S. Pat. Nos. 3,959,485, 3,839,584 and 3,868,461 and 3,959,485 all disclose the use of chemically modified sympathomimetic amines in the treatment of glaucoma and other ailments receptive to sympthomimetic amine activity. Specifically, the dipivaloxy derivatives of epinephrine and isoproterenol are disclosed.
U.S. Pat. No. 3,922,348 discloses successful treatment of glaucoma with a compound designated as 3,4-dihydroxy-2-(isopropylamino) acetophenone, the corresponding ketone derivative of isoproterenol. A review of the reference reveals that a high concentration (3%) is needed to achieve the desired result. Additionally, mydriatic activity is termed a toxic, harmful or deleterious side-effect.
Ocular tissues have the ability to metabolize a wide variety of drugs and foreign chemicals (powerful metabolic system for the biotransformation of exogenous substances). Since the eye is a relatively isolated organ that tends to retain or concentrate compounds within itself as described by Shichi and Nebert in Extrahepatic Metabolism of Drugs and Other Foreign Compounds (Gram, T., ed.) 333-363, S.P. Medical and Scientific Books, New York (1980),compounds applied or carried by the bloodstream to the eye must be detoxified. Considering that the uveal (iris-ciliary body) tissues have the largest blood flow of any tissue in the body, it seems reasonable that these tissues would have the best developed drug metabolizing system found in the eye. This has been substantiated by a number of research groups. Das, and Shichi, Expt. Eye Res., 33, 525-533 (1981). Drug metabolism by reduction of ketones and aldehydes has been established to be a preferential enzymatic pathway in mammals. Felsted and Bachur, Drug Meta. Rev., 11, 1-60 (1980); Ahmed, Felsted and Bachur, J. Pharmacol Exp. Ther., 209, 12-19 (1979). This process simultaneously eliminates lipid-soluble carbonyls and transforms them into alcohols that are significantly more polar and prepares the substrate for conjugation and elimination.
In most studies dealing with the transport and the disposition of topically applied ophthalmic agents, the anterior chamber has been considered to be the target area. Patton in Ophthalmic Drug Delivery Systems (Robinson ed.) Symposium Proceedings of Academy of Pharm. Sci., Chapter 2, 28-54, Washington D.C. (1980). However, since the iris-ciliary body appears to be one of the major sites of drug metabolism in the eye, it is considered to be the target tissue and its response with time can be assumed to reflect the amount of drug present.
The concept of developing methods for site-specific delivery of biologically active agents is highly desirable to improve efficacy and decrease toxicity. Although a lot of work has been done in this area, very few examples have promised simple and successful solutions. Shaw, Annu. Rep. Med. Chem., 15, 302 (1980) and Bodor and Farag, J. Med. Chem., 26, 313-318 (1983).
Adrenalone delivered at high concentrations will not produce mydriasis, either directly or indirectly. R. Weekers, et al, supra; Bodor and Visor, Exp. Eye Res., 38, 621-626 (1984). Thus, topical administration of adrenalone results only in adrenalone delivery which is not reduced in the eye to the active adrenalin.
High ocular sympathomimetic activity of some adrenalone diesters, such as the diisovaleryl and dipivalyl derivatives were described by Bodor, Kaminsk and Roller, supra, and found to be more potent on a molar basis than the successful prodrug of epinephrine, dipivalyl epinephrine. U.S. Pat. No. 4,094,983 discloses a method for reducing intraocular pressure using the adrenalone diester dipivalyl by the present inventor of record. A review of the reference reveals that the compound did not achieve faster recovery of normal vision.
Prior studies were primarily directed to attempting to reduce intraocular pressure with a concomitant diminution mydriatic effect. While a mydriatic effect is useful for lowering intraocular pressure associated with glaucoma, it results in vision impairment which is considered an undesirable effect, whether a single or multiple drug dose is required. However, for ophthalmic examinations and various surgical procedures, as well as a short-term reduction in intraocular pressure, a need exists for a method to produce a dramatic mydriatic effect and to reduce the time it takes for recovery of normal pupil diameter and vision while remaining essentially free from the deleterious disadvantages associated with previously used compounds.